Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Bone morphogenetic protein signaling in musculoskeletal cancer



Bone morphogenetic proteins (BMPs) belong to the transforming growth factor-β (TGF-β) superfamily of proteins; they were initially named after their ability to induce ectopic bone formation. Published studies have proved BMPs’ role in a variety of biological processes such as embryogenesis and patterning of body axes, and maintaining adult tissue homeostasis. Other studies have focused on BMPs properties, functions and possible involvement in skeletal diseases, including cancer.


A literature search mainly paying attention to the role of BMPs in musculoskeletal tumors was performed in electronic databases.


This article discusses BMPs synthesis and signaling, and summarizes their prominent roles in the skeletal system for the differentiation of osteoblasts, osteocytes and chondrocytes.


The review emphasizes on the role of BMP signaling in the initiation and progression of musculoskeletal cancer.

This is a preview of subscription content, log in to check access.

Fig. 1


  1. Alarmo EL, Korhonen T, Kuukasjarvi T, Huhtala H, Holli K, Kallioniemi A (2008) Bone morphogenetic protein 7 expression associates with bone metastasis in breast carcinomas. Ann Oncol 19(2):308–314

  2. Alarmo EL, Parssinen J, Ketolainen JM, Savinainen K, Karhu R, Kallioniemi A (2009) BMP7 influences proliferation, migration, and invasion of breast cancer cells. Cancer Lett 275(1):35–43

  3. Biver E, Hardouin P, Caverzasio J (2013) The “bone morphogenic proteins” pathways in bone and joint diseases: translational perspectives from physiopathology to therapeutic targets. Cytokine Growth Factor Rev 24(1):69–81

  4. Bobacz K, Gruber R, Soleiman A, Erlacher L, Smolen JS, Graninger WB (2003) Expression of bone morphogenetic protein 6 in healthy and osteoarthritic human articular chondrocytes and stimulation of matrix synthesis in vitro. Arthritis Rheum 48(9):2501–2508

  5. Bobinac D, Maric I, Zoricic S, Spanjol J, Dordevic G, Mustac E et al (2005) Expression of bone morphogenetic proteins in human metastatic prostate and breast cancer. Croat Med J 46(3):389–396

  6. Boeuf S, Bovee JV, Lehner B, van den Akker B, van Ruler M, Cleton-Jansen AM et al (2012) BMP and TGFbeta pathways in human central chondrosarcoma: enhanced endoglin and Smad 1 signaling in high grade tumors. BMC Cancer 12:488

  7. Buijs JT, Rentsch CA, van der Horst G, van Overveld PG, Wetterwald A, Schwaninger R et al (2007) BMP7, a putative regulator of epithelial homeostasis in the human prostate, is a potent inhibitor of prostate cancer bone metastasis in vivo. Am J Pathol 171(3):1047–1057

  8. Buijs JT, van der Horst G, van den Hoogen C, Cheung H, de Rooij B, Kroon J et al (2012) The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation. Oncogene 31(17):2164–2174

  9. Chen JC, Yang ST, Lin CY, Hsu CJ, Tsai CH, Su JL et al (2014) BMP-7 enhances cell migration and alphavbeta3 integrin expression via a c-Src-dependent pathway in human chondrosarcoma cells. PLoS ONE 9(11):e112636

  10. Cheng H, Jiang W, Phillips FM et al (2003) Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs). J Bone Joint Surg Am 85A:1544–1552

  11. Cho TJ, Gerstenfeld LC, Einhorn TA (2002) Differential temporal expression of members of the transforming growth factor beta superfamily during murine fracture healing. J Bone Miner Res 17(3):513–520

  12. Clement JH, Raida M, Sanger J, Bicknell R, Liu J, Naumann A et al (2005) Bone morphogenetic protein 2 (BMP-2) induces in vitro invasion and in vivo hormone independent growth of breast carcinoma cells. Int J Oncol 27(2):401–407

  13. Constam DB, Robertson EJ (1999) Regulation of bone morphogenetic protein activity by pro domains and proprotein convertases. J Cell Biol 144(1):139–149

  14. Dai J, Keller J, Zhang J, Lu Y, Yao Z, Keller ET (2005) Bone morphogenetic protein-6 promotes osteoblastic prostate cancer bone metastases through a dual mechanism. Cancer Res 65(18):8274–8285

  15. Daluiski A, Engstrand T, Bahamonde ME, Gamer LW, Agius E, Stevenson SL et al (2001) Bone morphogenetic protein-3 is a negative regulator of bone density. Nat Genet 27(1):84–88

  16. De Robertis EM, Kuroda H (2004) Dorsal–ventral patterning and neural induction in Xenopus embryos. Annu Rev Cell Dev Biol 20:285–308

  17. Devlin RD, Du Z, Pereira RC, Kimble RB, Economides AN, Jorgetti V et al (2003) Skeletal overexpression of noggin results in osteopenia and reduced bone formation. Endocrinology 144(5):1972–1978

  18. Du J, Yang S, An D, Hu F, Yuan W, Zhai C et al (2009) BMP-6 inhibits microRNA-21 expression in breast cancer through repressing deltaEF1 and AP-1. Cell Res 19(4):487–496

  19. Duan X, Liang YY, Feng XH, Lin X (2006) Protein serine/threonine phosphatase PPM1A dephosphorylates Smad1 in the bone morphogenetic protein signaling pathway. J Biol Chem 281(48):36526–36532

  20. Feeley BT, Gamradt SC, Hsu WK, Liu N, Krenek L, Robbins P et al (2005) Influence of BMPs on the formation of osteoblastic lesions in metastatic prostate cancer. J Bone Miner Res 20(12):2189–2199

  21. Feeley BT, Krenek L, Liu N, Hsu WK, Gamradt SC, Schwarz EM et al (2006a) Overexpression of noggin inhibits BMP-mediated growth of osteolytic prostate cancer lesions. Bone 38(2):154–166

  22. Feeley BT, Liu NQ, Conduah AH, Krenek L, Roth K, Dougall WC et al (2006b) Mixed metastatic lung cancer lesions in bone are inhibited by noggin overexpression and Rank: Fc administration. J Bone Miner Res 21(10):1571–1580

  23. Feng XH, Derynck R (2005) Specificity and versatility in TGF-b signaling through Smads. Annu Rev Cell Dev Biol 21:659–693

  24. Fong YC, Li TM, Wu CM, Hsu SF, Kao ST, Chen RJ et al (2008) BMP-2 increases migration of human chondrosarcoma cells via PI3 K/Akt pathway. J Cell Physiol 217(3):846–855

  25. Garcia P, Pieruschka A, Klein M, Tami A, Histing T, Holstein JH et al (2012) Temporal and spatial vascularization patterns of unions and nonunions: role of vascular endothelial growth factor and bone morphogenetic proteins. J Bone Joint Surg Am 94(1):49–58

  26. Gazzerro E, Canalis E (2006) Bone morphogenetic proteins and their antagonists. Rev Endocr Metab Disord 7(1–2):51–65

  27. Gobbi G, Sangiorgi L, Lenzi L, Casadei R, Canaider S, Strippoli P et al (2002) Seven BMPs and all their receptors are simultaneously expressed in osteosarcoma cells. Int J Oncol 20(1):143–147

  28. Graham TR, Agrawal KC, Abdel-Mageed AB (2010) Independent and cooperative roles of tumor necrosis factor-alpha, nuclear factor-kappaB, and bone morphogenetic protein-2 in regulation of metastasis and osteomimicry of prostate cancer cells and differentiation and mineralization of MC3T3-E1 osteoblast-like cells. Cancer Sci 101(1):103–111

  29. Guo W, Gorlick R, Ladanyi M, Meyers PA, Huvos AG, Bertino JR et al (1999) Expression of bone morphogenetic proteins and receptors in sarcomas. Clin Orthop Relat Res 365:175–183

  30. Halbrooks PJ, Ding R, Wozney JM, Bain G (2007) Role of RGM coreceptors in bone morphogenetic protein signaling. J Mol Signal 2:4

  31. Heldin CH, Miyazono K, ten Dijke P (1997) TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390(6659):465–471

  32. Hemmati-Brivanlou A, Thomsen GH (1995) Ventral mesodermal patterning in Xenopus embryos: expression patterns and activities of BMP-2 and BMP-4. Dev Genet 17(1):78–89

  33. Hogan BL (1996) Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Genes Dev 10(13):1580–1594

  34. Horbelt D, Denkis A, Knaus P (2012) A portrait of Transforming Growth Factor beta superfamily signalling: background matters. Int J Biochem Cell Biol 44(3):469–474

  35. Hou CH, Hsiao YC, Fong YC, Tang CH (2009) Bone morphogenetic protein-2 enhances the motility of chondrosarcoma cells via activation of matrix metalloproteinase-13. Bone 44(2):233–242

  36. Hu F, Meng X, Tong Q, Liang L, Xiang R, Zhu T et al (2013) BMP-6 inhibits cell proliferation by targeting microRNA-192 in breast cancer. Biochim Biophys Acta 1832(12):2379–2390

  37. Huang H, Song TJ, Li X, Hu L, He Q, Liu M et al (2009) BMP signaling pathway is required for commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc Natl Acad Sci USA 106(31):12670–12675

  38. Jensen ED, Pham L, Billington CJ Jr, Espe K, Carlson AE, Westendorf JJ et al (2010) Bone morphogenic protein 2 directly enhances differentiation of murine osteoclast precursors. J Cell Biochem 109(4):672–682

  39. Katsuno Y, Hanyu A, Kanda H, Ishikawa Y, Akiyama F, Iwase T et al (2008) Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway. Oncogene 27(49):6322–6333

  40. Ketolainen JM, Alarmo EL, Tuominen VJ, Kallioniemi A (2010) Parallel inhibition of cell growth and induction of cell migration and invasion in breast cancer cells by bone morphogenetic protein 4. Breast Cancer Res Treat 124(2):377–386

  41. Kleeff J, Maruyama H, Ishiwata T, Sawhney H, Friess H, Buchler MW et al (1999) Bone morphogenetic protein 2 exerts diverse effects on cell growth in vitro and is expressed in human pancreatic cancer in vivo. Gastroenterology 116(5):1202–1216

  42. Kobayashi A, Okuda H, Xing F, Pandey PR, Watabe M, Hirota S et al (2011) Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J Exp Med 208(13):2641–2655

  43. Kwon H, Kim HJ, Rice WL, Subramanian B, Park SH, Georgakoudi I et al (2010) Development of an in vitro model to study the impact of BMP-2 on metastasis to bone. J Tissue Eng Regen Med 4(8):590–599

  44. Langenfeld EM, Langenfeld J (2004) Bone morphogenetic protein-2 stimulates angiogenesis in developing tumors. Mol Cancer Res 2(3):141–149

  45. Langenfeld EM, Calvano SE, Abou-Nukta F, Lowry SF, Amenta P, Langenfeld J (2003) The mature bone morphogenetic protein-2 is aberrantly expressed in non-small cell lung carcinomas and stimulates tumor growth of A549 cells. Carcinogenesis 24(9):1445–1454

  46. Le Page C, Ouellet V, Madore J, Ren F, Hudson TJ, Tonin PN et al (2006) Gene expression profiling of primary cultures of ovarian epithelial cells identifies novel molecular classifiers of ovarian cancer. Br J Cancer 94(3):436–445

  47. Leboy P, Grasso-Knight G, D’Angelo M, Volk SW, Lian JV, Drissi H et al (2001) Smad-Runx interactions during chondrocyte maturation. The Journal of bone and joint surgery American volume. 83-A(Suppl 1, Pt 1):S15–S22

  48. Li B, Yang Y, Jiang S, Ni B, Chen K, Jiang L (2012) Adenovirus-mediated overexpression of BMP-9 inhibits human osteosarcoma cell growth and migration through downregulation of the PI3 K/AKT pathway. Int J Oncol 41(5):1809–1819

  49. Lin J, Patel SR, Wang M, Dressler GR (2006) The cysteine-rich domain protein KCP is a suppressor of transforming growth factor beta/activin signaling in renal epithelia. Mol Cell Biol 26(12):4577–4585

  50. Luo K (2003) Negative regulation of BMP signaling by the ski oncoprotein. J Bone Joint Surg Am 85-A(Suppl 3):39–43

  51. Luo G, Hofmann C, Bronckers AL, Sohocki M, Bradley A, Karsenty G (1995) BMP-7 is an inducer of nephrogenesis, and is also required for eye development and skeletal patterning. Genes Dev 9(22):2808–2820

  52. Luo X, Chen J, Song WX, Tang N, Luo J, Deng ZL et al (2008) Osteogenic BMPs promote tumor growth of human osteosarcomas that harbor differentiation defects. Lab Invest 88(12):1264–1277

  53. Lv Z, Yang D, Li J, Hu M, Luo M, Zhan X et al (2013) Bone morphogenetic protein 9 overexpression reduces osteosarcoma cell migration and invasion. Mol Cells 36(2):119–126

  54. Masuda H, Fukabori Y, Nakano K, Takezawa Y, csuzuki T, Yamanaka H (2003) Increased expression of bone morphogenetic protein-7 in bone metastatic prostate cancer. Prostate 54(4):268–274

  55. Mehdi R, Shimizu T, Yoshimura Y, Gomyo H, Takaoka K (2000) Expression of bone morphogenetic protein and its receptors in osteosarcoma and malignant fibrous histiocytoma. Jpn J Clin Oncol 30(6):272–275

  56. Mikic B, van der Meulen MC, Kingsley DM, Carter DR (1995) Long bone geometry and strength in adult BMP-5 deficient mice. Bone 16(4):445–454

  57. Minina E, Wenzel HM, Kreschel C, Karp S, Gaffield W, McMahon AP et al (2001) BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation. Development. 128(22):4523–4534

  58. Miyazono K (1999) Signal transduction by bone morphogenetic protein receptors: functional roles of Smad proteins. Bone 25(1):91–93

  59. Mohseny AB, Cai Y, Kuijjer M, Xiao W, van den Akker B, de Andrea CE et al (2012) The activities of Smad and Gli mediated signalling pathways in high-grade conventional osteosarcoma. Eur J Cancer 48(18):3429–3438

  60. Moustakas A, Heldin CH (2002) From mono- to oligo-Smads: the heart of the matter in TGF-beta signal transduction. Genes Dev 16(15):1867–1871

  61. Murakami G, Watabe T, Takaoka K, Miyazono K, Imamura T (2003) Cooperative inhibition of bone morphogenetic protein signaling by Smurf1 and inhibitory Smads. Mol Biol Cell 14(7):2809–2817

  62. Naber HP, Wiercinska E, Pardali E, van Laar T, Nirmala E et al (2012) BMP-7 inhibits TGF-beta-induced invasion of breast cancer cells through inhibition of integrin beta(3) expression. Cell Oncol (Dordr). 35(1):19–28

  63. Nakase T, Miyaji T, Tomita T, Kaneko M, Kuriyama K, Myoui A et al (2003) Localization of bone morphogenetic protein-2 in human osteoarthritic cartilage and osteophyte. Osteoarthr Cartil 11(4):278–284

  64. Nguyen A, Scott MA, Dry SM, James AW (2014) Roles of bone morphogenetic protein signaling in osteosarcoma. Int Orthop 38(11):2313–2322

  65. Nishida Y, Knudson CB, Knudson W (2004) Osteogenic Protein-1 inhibits matrix depletion in a hyaluronan hexasaccharide-induced model of osteoarthritis. Osteoarthr Cartil 12(5):374–382

  66. Nohe A, Hassel S, Ehrlich M, Neubauer F, Sebald W, Henis YI et al (2002) The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways. J Biol Chem 277(7):5330–5338

  67. Ogose A, Motoyama T, Hotta T, Watanabe H (1996) Expression of bone morphogenetic proteins in human osteogenic and epithelial tumor cells. Pathol Int 46(1):9–14

  68. Onichtchouk D, Chen YG, Dosch R, Gawantka V, Delius H, Massague J et al (1999) Silencing of TGF-beta signalling by the pseudoreceptor BAMBI. Nature 401(6752):480–485

  69. Rahman MS, Akhtar N, Jamil HM, Banik RS, Asaduzzaman SM (2015) TGF-β/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation. Bone Res. 3:15005

  70. Raida M, Clement JH, Leek RD, Ameri K, Bicknell R, Niederwieser D et al (2005) Bone morphogenetic protein 2 (BMP-2) and induction of tumor angiogenesis. J Cancer Res Clin Oncol 131(11):741–750

  71. Raval P, Hsu HH, Schneider DJ, Sarras MP Jr, Masuhara K, Bonewald LF et al (1996) Expression of bone morphogenetic proteins by osteoinductive and non-osteoinductive human osteosarcoma cells. J Dent Res 75(7):1518–1523

  72. Ren W, Sun X, Wang K, Feng H, Liu Y, Fei C et al (2014) BMP9 inhibits the bone metastasis of breast cancer cells by downregulating CCN2 (connective tissue growth factor, CTGF) expression. Mol Biol Rep 41(3):1373–1383

  73. Rojnik M, Jevnikar Z, Mirkovic B, Janes D, Zidar N, Kikelj D et al (2011) Cathepsin H indirectly regulates morphogenetic protein-4 (BMP-4) in various human cell lines. Radiol Oncol. 45(4):259–266

  74. Ross S, Cheung E, Petrakis TG, Howell M, Kraus WL, Hill CS (2006) Smads orchestrate specific histone modifications and chromatin remodeling to activate transcription. EMBO J 25:4490–4502

  75. Rubio R, Abarrategi A, Garcia-Castro J, Martinez-Cruzado L, Suarez C, Tornin J et al (2014) Bone environment is essential for osteosarcoma development from transformed mesenchymal stem cells. Stem Cells 32(5):1136–1148

  76. Sakai H, Furihata M, Matsuda C, Takahashi M, Miyazaki H, Konakahara T et al (2012) Augmented autocrine bone morphogenic protein (BMP) 7 signaling increases the metastatic potential of mouse breast cancer cells. Clin Exp Metastasis 29(4):327–338

  77. Secondini C, Wetterwald A, Schwaninger R, Thalmann GN, Cecchini MG (2011) The role of the BMP signaling antagonist noggin in the development of prostate cancer osteolytic bone metastasis. PLoS ONE 6(1):e16078

  78. Shu B, Zhang M, Xie R, Wang M, Jin H, Hou W et al (2011) BMP2, but not BMP4, is crucial for chondrocyte proliferation and maturation during endochondral bone development. J Cell Sci 124(Pt 20):3428–3440

  79. Sieber C, Kopf J, Hiepen C, Knaus P (2009) Recent advances in BMP receptor signaling. Cytokine Growth Factor Rev 20(5–6):343–355

  80. Singh A, Morris RJ (2010) The Yin and Yang of bone morphogenetic proteins in cancer. Cytokine Growth Factor Rev 21(4):299–313

  81. Solloway MJ, Dudley AT, Bikoff EK, Lyons KM, Hogan BL, Robertson EJ (1998) Mice lacking Bmp6 function. Dev Genet 22(4):321–339

  82. Sulzbacher I, Birner P, Trieb K, Pichlbauer E, Lang S (2002) The expression of bone morphogenetic proteins in osteosarcoma and its relevance as a prognostic parameter. J Clin Pathol 55(5):381–385

  83. Suzuki A, Raya A, Kawakami Y, Morita M, Matsui T, Nakashima K et al (2006) Nanog binds to Smad1 and blocks bone morphogenetic protein-induced differentiation of embryonic stem cells. Proc Natl Acad Sci USA 103(27):10294–10299

  84. Takahashi N, Maeda K, Ishihara A, Uehara S, Kobayashi Y (2011) Regulatory mechanism of osteoclastogenesis by RANKL and Wnt signals. Front Biosci (Landmark Ed) 16:21–30

  85. Tian G, Zhang G, Tan YH (2013) Calcitonin gene-related peptide stimulates BMP-2 expression and the differentiation of human osteoblast-like cells in vitro. Acta Pharmacol Sin 34(11):1467–1474

  86. Tsuji K, Bandyopadhyay A, Harfe BD, Cox K, Kakar S, Gerstenfeld L et al (2006) BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nat Genet 38(12):1424–1429

  87. Urist MR (1965) Bone: formation by autoinduction. Science 150(3698):893–899

  88. Valcourt U, Kowanetz M, Niimi H, Heldin CH, Moustakas A (2005) TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol Biol Cell 16(4):1987–2002

  89. Virk MS, Alaee F, Petrigliano FA, Sugiyama O, Chatziioannou AF, Stout D et al (2011) Combined inhibition of the BMP pathway and the RANK-RANKL axis in a mixed lytic/blastic prostate cancer lesion. Bone 48(3):578–587

  90. Wang L, Park P, Zhang H, La Marca F, Claeson A, Valdivia J et al (2011) BMP-2 inhibits the tumorigenicity of cancer stem cells in human osteosarcoma OS99-1 cell line. Cancer Biol Ther 11(5):457–463

  91. Wang L, Park P, La Marca F, Than K, Rahman S, Lin CY (2013) Bone formation induced by BMP-2 in human osteosarcoma cells. Int J Oncol 43(4):1095–1102

  92. Weiss KR, Cooper GM, Jadlowiec JA, McGough RL 3rd, Huard J (2006) VEGF and BMP expression in mouse osteosarcoma cells. Clin Orthop Relat Res 450:111–117

  93. Yamashita M, Ying SX, Zhang GM, Li C, Cheng SY, Deng CX et al (2005) Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation. Cell 121(1):101–113

  94. Yang S, Zhong C, Frenkel B, Reddi AH, Roy-Burman P (2005) Diverse biological effect and Smad signaling of bone morphogenetic protein 7 in prostate tumor cells. Cancer Res 65(13):5769–5777

  95. Yang X, Wang YP, Liu FX, Zeng K, Qian MQ, Chen G et al (2013) Increased invasiveness of osteosarcoma mesenchymal stem cells induced by bone-morphogenetic protein-2. In Vitro Cell Dev Biol Anim 49(4):270–278

  96. Ye L, Lewis-Russell JM, Kynaston H, Jiang WG (2007) Endogenous bone morphogenetic protein-7 controls the motility of prostate cancer cells through regulation of bone morphogenetic protein antagonists. J Urol 178(3 Pt 1):1086–1091

  97. Ye L, Kynaston H, Jiang WG (2009) Bone morphogenetic protein-10 suppresses the growth and aggressiveness of prostate cancer cells through a Smad independent pathway. J Urol 181(6):2749–2759

  98. Ye L, Bokobza S, Li J, Moazzam M, Chen J, Mansel RE et al (2010) Bone morphogenetic protein-10 (BMP-10) inhibits aggressiveness of breast cancer cells and correlates with poor prognosis in breast cancer. Cancer Sci 101(10):2137–2144

  99. Yeh LC (2010) In vitro and in vivo studies on the effects of bone morphogenetic protein-7 on human kidney and lung tumor cells. Int J Biomed Sci 6(3):176–181

  100. Yoshida Y, Tanaka S, Umemori H, Minowa O, Usui M, Ikematsu N et al (2000) Negative regulation of BMP/Smad signaling by Tob in osteoblasts. Cell 103(7):1085–1097

  101. Yoshikawa H, Takaoka K, Masuhara K, Ono K, Sakamoto Y (1988) Prognostic significance of bone morphogenetic activity in osteosarcoma tissue. Cancer 61(3):569–573

  102. Yoshikawa H, Rettig WJ, Lane JM, Takaoka K, Alderman E, Rup B et al (1994a) Immunohistochemical detection of bone morphogenetic proteins in bone and soft-tissue sarcomas. Cancer 74(3):842–847

  103. Yoshikawa H, Rettig WJ, Takaoka K, Alderman E, Rup B, Rosen V et al (1994b) Expression of bone morphogenetic proteins in human osteosarcoma. Immunohistochemical detection with monoclonal antibody. Cancer 73(1):85–91

  104. Yu Y, Harris RI, Yang JL, Anderson HC, Walsh WR (2004) Differential expression of osteogenic factors associated with osteoinductivity of human osteosarcoma cell lines. J Biomed Mater Res A 70(1):122–128

  105. Zehentner BK, Dony C, Burtscher H (1999) The transcription factor Sox9 is involved in BMP-2 signaling. J Bone Miner Res 14(10):1734–1741

  106. Zhang YE (2009) Non-Smad pathways in TGF-beta signaling. Cell Res 19(1):128–139

  107. Zhang MY, Wu J, Gong X, Chen RK, Fang JS (2009) Clinical significance of BMP-2 protein and mRNA expression in human glioma. Chin J Cell Mol Immunol 25(7):637–639

  108. Zhao GQ (2003) Consequences of knocking out BMP signaling in the mouse. Genesis 35(1):43–56

  109. Zhou H, Hammonds RG Jr, Findlay DM, Fuller PJ, Martin TJ, Ng KW (1991) Retinoic acid modulation of mRNA levels in malignant, nontransformed, and immortalized osteoblasts. J Bone Miner Res 6(7):767–777

Download references

Author information

Correspondence to Andreas F. Mavrogenis.

Ethics declarations

Conflict of interest

None of the authors had any financial or personal relationships with other people or organizations that could inappropriately influence (bias) their work. Myrto Bami, Andrea Angelini, Mandy Milonaki, Evanthia Mitsiokapa, Dimitrios Stamoulis, Andreas F. Mavrogenis, Panayotis N. Soucacos declares that they have no conflict of interest.

Ethical standard

This article does not contain any studies with human participants or animals performed by any of the authors.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bami, M., Mavrogenis, A.F., Angelini, A. et al. Bone morphogenetic protein signaling in musculoskeletal cancer. J Cancer Res Clin Oncol 142, 2061–2072 (2016). https://doi.org/10.1007/s00432-016-2149-9

Download citation


  • Bone morphogenetic proteins
  • Cancer
  • Musculoskeletal
  • Bone tumors